Cytokines are known to play important roles in maintaining the homeostasis of cardiac muscle. In particular, leukemia inhibitory factor (LIF), an interleukin 6 (IL-6) family cytokine, is reported to have a role in the signal transduction into cardiac cells via the gp130 (glycoprotein 130)/JAK pathway, providing various effects such as heart protection, angiogenesis, and hypertrophy of cardiomyocytes (Non-Patent Documents 1 and 2). However, because LIF strongly induces inflammation (Non-Patent Document 3), a cytokine therapy for cardiovascular disease using LIF is generally considered difficult. Specifically, the use of LIF in drug applications is considered impractical because of its side effects such as fever.
In addition to LIF, the IL-6 cytokine family includes IL-6, cardiotrophin-1, oncostatin M, and interleukin 11 (hereinafter, also referred to as “IL-11”). All of these cytokines are known to activate the downstream signal transduction system through binding to their specific α receptors and to the common β chain gp130 (Non-Patent Document 4). While these cytokines share the same signaling pathways, and are functionally redundant, they also show completely different effects, as reported in Non-Patent Document 5. By probing for myocardial cytokines that share the same signal transduction system with LIF but are less inflammatory, it would be possible to establish a novel cytokine therapy for cardiovascular disease.
The effects of IL-11 as an anti-inflammatory cytokine have been reported (Non-Patent Document 6). Further, IL-11, a platelet growth factor, has been approved in the United States as a therapeutic agent for thrombocytopenia in cancer chemotherapy, and the efficacy and safety of IL-11 has been reported (Non-Patent Document 7). In Japan, clinical trials are underway for thrombocytopenia in cancer chemotherapy, and certain information is available concerning the safety of IL-11 (Non-Patent Documents 8 and 9). However, the effects of IL-11 on the cardiovascular system have not been fully studied, and no efforts have been made concerning the application of IL-11 to cardiovascular disease.
In Patent Document 1, IL-11 is described as having anti-inflammatory effects, and therefore being effective for various disorders including reperfusion injury after myocardial infarction. However, the publication does not include any example that actually demonstrates the efficacy of IL-11 in reperfusion injury after myocardial infarction, and it is unclear whether IL-11 actually has therapeutic effects on heart diseases.
Non-Patent Document 1: Circulation. 2003; 108:748-753.
Non-Patent Document 2: J Biol Chem. 1996; 271:9535-45.
Non-Patent Document 3: Stem Cells. 1999; 17:127-37.
Non-Patent Document 4: Annu Rev Immunol. 1997; 15:797-819.
Non-Patent Document 5: Ann. N.Y. Acad. Sci. 1998; 856:12-21.
Non-Patent Document 6: J. Immunol. 1996; 157:3627-3634.
Non-Patent Document 7: Blood. 1996; 87:3615-3624.
Non-Patent Document 8: Gan To Kagaku Ryoho. 2005; 32:489-96.
Non-Patent Document 9: Gan To Kagaku Ryoho. 2005; 32:479-87.
Patent Document 1: JP-T-11-508556